ITMI971211A1 - PRODUCTION FOR THE PREPARATION OF A DESOXYURIDINE DERIVATIVE - Google Patents

Description

Description of the industrial invention

The present invention relates to a process for the preparation of a derivative of deoxyuridine. More particularly, the invention relates to a process for the preparation of 5'-deoxy-5-fluorouridine.

The compound 5'-deoxy-5-fluorouridine is a cytostatic agent known by its International Common Name doxifluridine.

Doxifluridine, having the formula I,

(THE)

is cited in US 4,071,680, in which a multi-step synthesis is described which, starting from 5-fluorouridine, involves the elimination of the 5'-hydroxyl group through the corresponding 5'-iododerivative, obtained using triphenylphosphite methyldide as an iodifying agent, which requires particular precautions for the toxicity of the reagent and for the formation of the reaction by-products.

Patent EP 21,231 describes the preparation of doxifluridine by removing the acyl groups from the corresponding 2 ', 3'-diesters with carboxylic acids, that is, from the corresponding 2', 3'-diacetal. However, the synthesis of the starting product involves the replacement of the hydroxyl group with a bromine atom and the transformation of the bromoderivative into the corresponding deoxy compound by catalytic hydrogenation. Also in this case, the bromination is carried out with the use of a phosphorus compound, that is with bromine in the presence of a relevant quantity of triphenylphosphine.

According to S. Aymera and P.V. Danenberg (J. Med. Chem. 1982, 25, 999), 5 '-deoxy-5'-iodo-2', 3'-O-isopropylidene-5-fluorouridine is prepared according to the method of Cook et al. (J. Med. Chem. 1979, 22, 1330), which corresponds to US patent 4,071,680. The same article describes the transformation of 5'-deoxy-5'-O-methanesulfonyloxy-2 ', 3'-O-isopropylidene-5-fluorouridine into 5'-bromo-5'-deoxy-2', 3'-O -isopropic liden-5-fluorouridine with lithium bromide, but does not indicate any further transformation.

On the other hand, in the aforementioned patent EP 21,231, the replacement of a bromine atom with a hydrogen atom is carried out by catalytic hydrogenation in the presence of potassium hydroxide on a substrate not containing the uracil nucleus, the latter being introduced after the preparation of the deoxy-sugar in the presence of a strong inorganic base.

It has now been found that it is possible to replace the hydroxyl group of the 2 ', 3'-isopropylidene-5-fluorouridine with an iodine atom, in the absence of a phosphorus compound, if the aforesaid hydroxyl group is previously activated as a sulphonic ester.

It has also been found that the iodine atom of 5'-deoxy-5'-iodo-2 ', 3'-O-isopropylidene-5-fluorouridine can be replaced with a hydrogen atom by catalytic hydrogenation without the use of bases strong, thus obtaining the corresponding 5'-deoxy compound with excellent yields. The same substitution can take place with other hydrogen donors, such as cyclohexene or cyclohexadiene, or a hydride, for example tributyltin hydride.

Thus, the present invention relates to a process for the preparation of 5'-deoxy-5-fluorouridine, characterized in that:

(a) it is the 2 ', 3'-O-isopropyliden-5-fluorouridine of formula II

(II)

with a functional derivative of a sulphonic acid of formula III

R— SO3H (III) wherein R is a (C1-C4) alkyl, trifluoromethyl, unsubstituted or mono-, di- or trisubstituted phenyl group;

(b) the resulting 5'-O-sulfonate derivative of formula IV in which R has the above defined meaning is treated with an alkaline or alkaline-earth iodide;

(c) 5 '-deoxy-5'-iodo-2', 3'-O-isopropylidene-5-fluorouridine of formula V is hydrolyzed

thus obtained in an acid medium; And

(d) 5'-deoxy-5'-iodo-5-fluorouridine of formula VI is submitted

to a reduction with hydrogen or a hydrogen donor.

In formula III, R is preferably methyl, ethyl, n-butyl, trifluoromethyl, phenyl, monosubstituted phenyl, for example with a methyl, methoxy, nitro or halogen group, disubstituted, for example with a methyl group, or trisubstituted, for example with a methyl group, in particular 2,4,6-trisubstituted.

Chloride, anhydride or a mixed anhydride is conveniently used as a functional derivative of sulphonic acid. Particularly preferred as esterifying agents are methanesulfonyl chloride and benzenesulfonyl chloride, p-toluenesulfonyl chloride, trifluoro methanesulfonyl chloride and 2,4,6-trimethylphenylsulfonyl chloride.

Thus, in step (a), the functional derivative of the sulphonic acid of formula III, preferably selected from the group defined above, is treated with 2 ', 3'-O-isopropylidene-5-fluorouridine. Advantageously, the reaction is carried out in an organic solvent, for example a halogenated solvent such as dichloromethane, 1,2-dichloroethane or 1,1,1-trichloroethane, or a polar aprotic solvent, such as N, N-dimethylformamide, N, N- dimethylacetamide, dimethyl sulfoxide or acetonitrile, or ethyl acetate or an aromatic hydrocarbon such as toluene or xylene, in the presence of a base such as trimethylamine, triethylamine, diisopropylamine, N-ethyldiisopropylamine, pyridine or dimethylaminopyridine.

In general, after 5 ÷ 6 hours at a temperature of 0 ÷ + 40 ° C, the reaction is complete and the compound of formula IV thus obtained is separated by simple filtration, after treatment with water.

The 5'-O-sulfonate derivative of formula IV can also be recovered by extraction with an organic solvent, isolation and characterization according to conventional methods.

Alternatively, the concentrated solution can be directly used in step (b).

Step (b) is carried out by simply treating the compound of formula IV, in pure form or in concentrated solution obtained at the end of step (a), with an alkaline or alkaline-earth iodide in an organic solvent such as a ketone, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, preferably dioxane or tetrahydrofuran or an aprotic polar solvent, preferably acetonitrile, N, N-dimethylformamide, Ν, Ν-dimethylacetamide or dimethyl sulfoxide.

After 4 ÷ 6 hours at a temperature of 40 ÷ 80 ° C, the reaction is complete and, as in step (a), the by-products of the reaction are separated by filtration. The desired final product, i.e. 5'-deoxy-5 '-iode-2', 3'-O-isopropylidene-5-fluorouridine of formula V can be extracted with an organic solvent, preferably ethyl acetate, and subsequent concentration, and it can be isolated according to conventional methods. As in step (a), the concentrated solution containing the compound of formula V can be used directly in step (c).

Step (c) consists of a hydrolysis of 5'-deoxy-5'-iodo-2 ', 3'-O-isopropylidene-5-fluorouridine in an acid medium according to the methods commonly used in sugar chemistry, more particularly in that of nucleosides. Preferably, this hydrolysis is carried out in aqueous formic acid or, more advantageously, in aqueous acetic acid, or in N, N-dimethylformamide or N, N-dimethylacetamide in the presence of aqueous HCl, at a temperature of 80 + 100 ° C.

The 5'-deoxy-5'-iodo-5-fluorouridine of formula VI thus obtained is isolated by evaporation of the solvent and extraction of the residue with a suitable solvent, preferably ethyl acetate.

As specified above, the compounds obtained at the end of steps (a) and (b) can be isolated and characterized, or, preferably, they can be used without isolation and therefore in the raw state, except for possible concentration and substitution of the reaction medium. The yields of the three steps are very high, always higher than 90% of the theoretical one and the compound of formula VI is recovered with yields of the order of 83 + 85%, calculated with respect to 2 ', 3'-O-isopropylidene-5 -fluorouridine of starting formula II.

In step (d) the compound of formula VI is subjected to a reduction, which can be carried out by catalytic hydrogenation or with the use of cyclohexene or cyclohexadiene as hydrogen donors, for example in the presence of Pd / C, preferably at 5% , as a catalyst, or even with a hydride.

The reduction is carried out in an organic solvent, for example an alcohol or in a mixture of alcohols, such as methanol, ethanol, propanol, isopropanol or n-butanol. Preferably, an organic base, such as trimethylamine, triethylamine, diisopropylamine, pyridine or dimethylaminopyridine, or an inorganic base such as sodium bicarbonate or potassium bicarbonate is present in the reaction medium.

When the reduction is carried out with hydrogen, the hydrogenation proceeds at atmospheric pressure or at 1 + 2 bar and at room temperature, in the presence of 5% Pd / C.

When the reduction is carried out in the presence of a hydrogen donor, such as cyclohexene, cyclohexadiene or a hydride, for example tributyltin hydride, the reaction proceeds in an alcoholic solvent. such as methanol. ethanol. isopropanol, n-butanol, isobutanol, or in mixtures of the same solvents with an aprotic solvent, such as toluene.

More particularly, the reduction, when carried out with cyclohexene or cyclohexadiene as hydrogen donors at a temperature of 60 ÷ 90 ° C, is completed after 3 ÷ 6 hours.

The 5-deoxy-5-fluorouridine thus obtained is isolated according to conventional methods, more particularly by filtration of the catalyst and evaporation of the solvent. The final product is crystallized with an ethanol / isopropanol mixture = 3/2 (v / v).

When the reduction is carried out with the use of tributyltin hydride, the reaction takes place by dissolution of 5'-deoxy-5'-iodo-5-fluorouridine in an alcohol, for example methanol, by adding the reducing agent dissolved in toluene and reflux heating in the presence of α, α-azoisobutyronitrile in catalytic quantity. After 1 ÷ 3 hours the reduction is complete and, after evaporation of the solvent, the 5 '-deoxy-5-fluorouridine thus obtained is recovered according to conventional methods.

According to a preferential procedure of the present invention, steps (a), (b) and (c) are carried out without isolation of the product obtained at the end of each step (a) and (b). Thus, the process of the present invention allows the preparation of doxifluridine in a very easy way and with very high yields. Furthermore, this procedure can be carried out in four steps, requiring only two operations, according to the one-pot technique. The above process is illustrated in Scheme I, in which R is a (C1-C4) alkyl group, a trifluoromethyl, an unsubstituted or mono-, di- or trisubstituted phenyl group.

Scheme I

The following examples illustrate the invention without, however, limiting it.

Example 1

90.6 g (0.48 m) of p-toluenesulfonyl chloride. The mixture is stirred for 5 hours, then 10 l of water are slowly added and kept under stirring for 3 hours. After 15 hours at room temperature the precipitate is filtered, washed with water and dried. 99.2 g (83%) of 2 ', 3'-O-isopropylidene-5' -O- (p-toluenesulfonyl) -5-fluorouridine are obtained in crystalline form with m.p. = 154 ÷ 156 ° C, purity (HPLC) = 99.89% and [α] D = 26.71 ° (c = 1, CH3OH).

The product thus obtained can be purified by crystallization with ethanol to give a white crystalline powder with m.p. = 156 ÷ 158 ° C and purity = 99.9 + 100% (HPLC).

Example 2

A. 5'-deoxy-5'-iodo-5-fluorouridine

To a solution of 39.2 g (0.13 m) of 2 ', 3'-O-isopropylidene-5-fluorouridine in 55 ml of methylene chloride and 159 ml (1.98 m) of pyridine, cooled to 5 ° C, 60 g (0.315 m) of ptoluenesulfonyl chloride are added. It is kept under stirring for 5 hours and the formation of an abundant precipitate is noted. 160 ml of methylene chloride and 160 ml of water are added, while the temperature rises up to 40 ° C. The phases are separated and the organic one is extracted with about 900 ml of HC1 N; the organic phase is then washed with 2 x 100 ml of water. In the organic phase 0.117 m of 2 ', 3'-O-isopropylidene-5'-O- (ptoluenesulfonyl) -5-fluorouridine are present (yield - 90% of theoretical); it is concentrated under vacuum to an oily residue, which is taken up with 2 x 100 ml of acetone. The residual oil is treated with 600 ml of acetone and 105 g (0.70 m) of sodium iodide are added to the solution. The mixture is brought to reflux (57 ° C) and, after about 30 ', the precipitation begins. It is kept under reflux for 5 hours, then it is cooled, concentrated under vacuum and taken up with 2 x 80 ml of ethyl acetate. The residual oil is treated with 800 ml of ethyl acetate and 100 ml of water. The phases are separated, the aqueous one is extracted with 2 x 80 ml of ethyl acetate. The combined organic phases are washed with 2 x 100 ml of aqueous 5% sodium metabisulphite solution, then with 100 ml of water. In the organic phase, 0.113 m of 5'-deoxy-5'-iodo-2 ', 3'-O-isopropylidene-5-fluorouridine are present (yield ~ 97% of the theoretical). It is concentrated under vacuum to a small volume, 560 ml of 80% aqueous acetic acid are added to the residue and the temperature is brought to 95 ° C. After 4 hours of heating, a check by HPLC is carried out (0.34% of residual starting product). It is cooled, concentrated under vacuum to oil and taken up with 150 ml of ethyl acetate. It is left at 20-25 ° C for 15 hours. The product is filtered, washed with ethyl acetate and dried under vacuum at 45 ° C. 44.5 g of 5'-deoxy-5'-iodo-5-fluorouridine are obtained with m.p. = 174 + 175 ° C, purity (HPLC) = 99.74% and [α] D = 8.96 "(c = 1, CH3OH). From the mother liquors, concentrate the empty septum and recover with 50 ml of ethyl acetate, after 15 hours at 5 ° C, another 3.3 g of product are obtained Total yield: 83% of the theoretical value, calculated with respect to 2 ', 3'-O-isopropylidene-5-fluorouridine.

B. 5'-deoxy-5-fluorouridine

15.2 ml (0.108 m) of diisopropylamine are added to a suspension of 20 g (0.053 m) of 5'-deoxy-5'-iodo-5-fluoro uridine in a mixture of 60 ml of ethanol and 40 ml of isopropanol. , then 3 g of 5% Pd / C are added to the solution and subjected to hydrogen at a pressure of about 1 bar for 14 hours. The catalyst is removed by filtration and the filtrate is concentrated under vacuum to a residue. It crystallizes with a mixture of ethanol / isopropanol = 60/40 v / v; after 8 hours it is filtered, washed with the same mixture and dried under vacuum at 45 ° C for 15 hours. 11.6 g (yield ~ 89% of the theoretical) of 5 '-deoxy-5-fluorouridine are obtained with m.p. = 187 + 188 ° C, purity (HPLC) = 99.75% and [α] D = 18.2 ° (c = 0.42, H2O).

Example 3

105 g of sodium iodide and the clear solution obtained is heated under reflux for 4 + 5 hours. It is cooled, filtered and washed with acetone. The combined acetone solutions are concentrated under vacuum to a residue, which is taken up with 3500 ml of ethyl acetate. After washing with 500 ml of aqueous 3% sodium metabisulphite solution, then with water, the solution is concentrated in ethyl acetate up to a small volume. After 15 hours the precipitate is filtered and dried to give 33.2 g of 5'-deoxy-5'-iodo-2 ', 3'-O-isopropyliden-5-fluorouridine, in the form of a white crystalline powder with m.p. = 199 ÷ 202 ° C, purity (HPLC) = 99.9% and [α] D = -16.8 "(c = 0.50, CH3OH).

Example 4

A. 5'-deoxy-5'-iodo-5-fluorouridine

A suspension of 51 g (0.105 m) of 5'deoxy-5 '-iodo-2', 3'-O-isopropyliden-5-fluorouridine in 500 ml of acetic acid and 120 ml is heated at 95 ° C for 90 ' of water. The solution obtained is concentrated under vacuum to a residue, which is taken up with 2 1 of ethyl acetate. It is concentrated to a small volume and, after 15 hours at room temperature, the precipitate is filtered, washed with ethyl acetate and dried to give 35.6 g of 5'-deoxy-5'-iodo-5-fluorouridine with m.p. = 174.5 ÷ 175.5 ° C, purity (HPLC) = 99.74% [α] D = 8.96 ° (c = 1.00, CH3OH).

B. 5'-deoxy-5-fluorouridine

A solution of 37.4 g of tributyltin hydride in 310 ml of toluene. The mixture is heated under reflux for 2 hours and the clear solution obtained is concentrated under vacuum to a semisolid residue, which is dispersed with 900 ml of petroleum ether. The solid is filtered and treated with 1200 ml of water; the tin salts are separated by filtration and the filtrate is concentrated under vacuum; the residue is crystallized with 500 ml of hot ethanol and 12.3 g of 5'-deoxy-5-fluorouridine are obtained with m.p. = 188 ÷ 189 ° C, purity (HPLC) = 99.91% and [α] D = 18.4 ° (c = 0.42, H2O).

Example 5

6 ml of cyclohexene (0.06m) and 14ml (0.1m) of triethylamine. It is heated to 60 ° C to have complete solubilization, then 1.5 g Pd / C 5% are added. The temperature is brought to 80 ° C and maintained at this temperature for 5 hours. It is filtered while hot, washing with hot n-butanol; it is concentrated under vacuum to a residue, which crystallizes with a mixture of 60 ml of ethanol and 4 ml of isopropanol. 4.5 g of 5'-deoxy-5-fluorouridine are obtained with m.p. = 188 ÷ 189 ° C, purity (HPLC) = 99.87% and [α] D = 18.35 ° (c = 0.42, H2O).

Claims (15)

CLAIMS 1. Process for the preparation of 5'-deoxy-5-fluorouridine of formula I characterized by the fact that: (a) it is the 2 ', 3'-O-isopropyliden-5-fluorouridine of formula II with a functional derivative of a sulphonic acid of formula III wherein R is a (C1C4) alkyl, trifluoromethyl, unsubstituted or mono-, di- or trisubstituted phenyl group; (b) the resulting 5'-O-sulfonate derivative of formula IV is treated in which R has the meaning defined above, with an alkaline or alkaline-terrous iodide; (c) 5 '-deoxy-5' -iodo-2 ', 3'-O-isopropylidene-5-fluorouridine of formula V is hydrolyzed thus obtained in an acid medium; And (d) the 5'-deoxy-5-iodo-5-fluorouridine of formula VI is subjected to a reduction. 2. Process according to claim 1, characterized in that, in formula III of said sulphonic acid, R is methyl, ethyl, n-butyl, trifluoromethyl, phenyl, monosubstituted phenyl, for example with a methyl, methoxy, nitro or halogen group , disubstituted, for example with two methyl groups, or trisubstituted, for example with three methyl groups, in particular 2,4,6-trisubstituted. 3. Process according to claim 1, in which, in step (a), chloride, anhydride or a mixed anhydride is used as a functional derivative of the sulphonic acid of formula III. 4. Process according to claim 3, characterized in that the functional derivative of the acid of formula III is methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride or 2,4,6-trimethylphenylsulfonyl chloride. 5. Process according to claim 1, wherein the steps (a), (b) and (c) are carried out without isolation of the products obtained at the end of each of the steps (a) and (b). 6. Process according to claim 1, wherein the reduction of step (d) is carried out by catalytic hydrogenation. 7. Process according to claim 6, wherein palladium on carbon is used as a catalyst in the catalytic hydrogenation. 8. Process according to claim 7, wherein said catalytic hydrogenation is carried out in the presence of a base. 9. Process according to claim 8, wherein said base is a secondary or tertiary amine. 10. Process according to claim 9, wherein said secondary or tertiary amine is trimethylamine, triethylamine, diisopropylamine, N-ethyldiisopropylamine, pyridine or dimethylaminopyridine. 11. Process according to claim 8, wherein said base is sodium bicarbonate. 12. Process according to claim 6, wherein tributyltin hydride is used as the reducing agent. 13. Process according to claim 12, wherein the reduction is carried out in the presence of a promoter, in particular α, αazoisobutyronitrile. 14. A process according to claim 6, wherein the reduction is carried out by means of cyclohexene or cyclohexadiene as a hydrogen donor. 15. Process according to claim 14, wherein said reduction step is carried out at a temperature between 60 ° C and 90 ° C.